The Presence of Sarcolipin Results in Increased Heat Production by Ca2+-ATPase

Mall, Sanjay; Broadbridge, Robert J.; Harrison, S.; Gore, Michael G.; Lee, Anthony G.; East, J. Malcolm

doi:10.1074/jbc.m606869200

Cited by 98 publications

(108 citation statements)

References 35 publications

(35 reference statements)

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“…The amount of SERCA1a and SERCA2a in EDL and soleus homogenates was determined from intensity of bands that fell within the linear range for samples of purified SERCA1a and SERCA2a on the same gel. (41). These results could be explained by SLN causing an increased rate of slippage on SERCAs (41, 51), which would decrease the fraction of energy released during ATP hydrolysis that is converted into work and increase the amount of heat released (16,17).…”

Section: Discussionmentioning

confidence: 99%

ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

Norris

Bombardier

Smith

et al. 2010

American Journal of Physiology-Cell Physiology

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Norris SM, Bombardier E, Smith IC, Vigna C, Tupling AR. ATP consumption by sarcoplasmic reticulum Ca 2ϩ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle. Am J Physiol Cell Physiol 298: C521-C529, 2010. First published December 16, 2009; doi:10.1152/ajpcell.00479.2009In this study, we aimed to directly quantify the relative contribution of Ca 2ϩ cycling to resting metabolic rate in mouse fast-twitch (extensor digitorum longus, EDL) and slow-twitch (soleus) skeletal muscle. Resting oxygen consumption of isolated muscles (V O2, l·g wet wt) measured polarographically at 30°C was ϳ25% higher in soleus (0.61 Ϯ .03) than in EDL (0.46 Ϯ .03). To quantify the specific contribution of Ca 2ϩ cycling to resting metabolic rate, cyclopiazonic acid (CPA), a highly specific inhibitor of sarco(endo)plasmic reticulum Ca 2ϩ ATPases (SERCAs), was added to the bath at different concentrations (1, 5, 10, and 15 M). There was a concentration-dependent effect of CPA on V O2, with increasing CPA concentrations up to 10 M resulting in progressively greater reductions in muscle V O2. There were no differences between 10 and 15 M CPA, indicating that 10 M CPA induces maximal inhibition of SERCAs in isolated muscle preparations. Relative reduction in muscle V O2 in response to CPA was nearly identical in EDL (1 M, 10.6 Ϯ 3.0%; 5 M, 33.2 Ϯ 3.4%; 10 M, 49.2 Ϯ 2.9%; 15 M, 50.9 Ϯ 2.1%) and soleus (1 M, 11.2 Ϯ 1.5%; 5 M, 37.7 Ϯ 2.4%; 10 M, 50.0 Ϯ 1.3%; 15 M, 49.9 Ϯ 1.6%). The results indicate that ATP consumption by SERCAs is responsible for ϳ50% of resting metabolic rate in both mouse fast-and slow-twitch muscles at 30°C. Thus SERCA pumps in skeletal muscle could represent an important control point for energy balance regulation and a potential target for metabolic alterations to oppose obesity. oxygen consumption; in vitro; isolated skeletal muscle; energy expenditure; calcium pump SKELETAL MUSCLE REPRESENTS ϳ40% of body weight and accounts for ϳ20 -30% of whole body basal metabolic rate (45, 60). Like other cell types, a portion of basal metabolic rate in skeletal muscle can be attributed to the cycling of Ca 2ϩ across cell membranes, but very few studies have attempted to quantify the relative contribution of Ca 2ϩ cycling to resting muscle metabolism. Under basal conditions in skeletal muscle, sarco-(endo)plasmic reticulum Ca 2ϩ -ATPases (SERCAs) are responsible for maintaining a Ͼ10 4 -fold Ca 2ϩ concentration gradient across the sarcoplasmic reticulum (SR) membrane and for keeping the cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] f ) at or below 100 nM (53). Under optimized states, SERCAs transport 2 mol of Ca 2ϩ across the SR membrane upon the hydrolysis of 1 mol of ATP (15,31, 51). Early estimates of the energy consumed by SERCAs in muscle under basal conditions were based on measurements of the rate of Ca 2ϩ efflux from isolated SR vesicles and then the amount of ATP that would be required to reuptake that Ca 2ϩ was calculated assuming an optimal Ca 2ϩ -to-ATP coupling ratio. This appr...

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Section: Discussionmentioning

confidence: 99%

ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

Norris

Bombardier

Smith

et al. 2010

American Journal of Physiology-Cell Physiology

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“…This uncoupling likely plays a physiological role (7). Like in the case of SERCA, it seems reasonable to expect uncoupled reactions in NKA under optimum substrate conditions.…”

Section: Discussionmentioning

confidence: 91%

“…This uncoupling is prominent in the presence of a Ca 2ϩ gradient across the SR membrane. Recent studies have shown that sarcolipin, a small SERCA regulator, increases heat production by this pump (7). This finding demonstrates a regulatory interaction affecting the conformational equilibrium toward SERCA isomer with an increased tendency to hydrolytic cleavage before Ca 2ϩ translocation.…”

mentioning

confidence: 86%

Capsazepine, a synthetic vanilloid that converts the Na,K-ATPase to Na-ATPase

Mahmmoud

2008

Proc. Natl. Acad. Sci. U.S.A.

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Capsazepine (CPZ), a synthetic capsaicin analogue, inhibits ATP hydrolysis by Na,K-ATPase in the presence but not in the absence of K ؉ . Studies with purified membranes revealed that CPZ reduced Na ؉ -dependent phosphorylation by interference with Na ؉ binding from the intracellular side of the membrane. Kinetic analyses showed that CPZ stabilized an enzyme species that constitutively occluded K ؉ . Low-affinity ATP interaction with the enzyme was strongly reduced after CPZ treatment; in contrast, indirectly measured interaction with ADP was much increased, which suggests that composite regulatory communication with nucleotides takes place during turnover. Studies with lipid vesicles revealed that CPZ reduced ATP-dependent digitoxigenin-sensitive 22 Na ؉ influx into K ؉ -loaded vesicles only at saturating ATP concentrations. The drug apparently abolishes the regulatory effect of ATP on the pump. Drawing on previous homology modeling studies of Na,K-ATPase to atomic models of sarcoplasmic reticulum Ca-ATPase and on kinetic data, we propose that CPZ uncouples an Na ؉ cycle from an Na ؉ /K ؉ cycle in the pump. The Na ؉ cycle possibly involves transport through the recently characterized Na ؉ -specific site. A shift to such an uncoupled mode is believed to produce pumps mediating uncoupled Na ؉ efflux by modifying the transport stoichiometry of single pump units.sodium pump ͉ uncoupling ͉ potassium occlusion N a,K-ATPase (NKA), a P-type cation pump (1), utilizes energy from ATP hydrolysis to exchange intracellular Na ϩ for extracellular K ϩ against their electrochemical potential gradients. The functional pump contains an ␣-subunit that undergoes substrateinduced conformational transitions, coupling ATP hydrolysis to ion transport, and a ␤-subunit important for maturation and targeting of the complex to the membrane (2).According to the Albers-Post scheme, occlusion of three intracellular Na ϩ ions promotes phosphorylation of the ␣-subunit from ATP, whereas occlusion of two extracellular K ϩ ions promotes dephosphorylation (2). Depending on the specific ionic composition on both sides of the membrane, the pump catalyzes several partial reactions (3). In the absence of K ϩ , NKA mediates ATP-driven Na ϩ transport processes, including exchange as well as uncoupled efflux (reviewed in ref. 4). Furthermore, in inside-out vesicles of human red cells, the ratio of net 22 Na ϩ influx/ 86 Rb ϩ efflux was reduced at sub-millimolar cytoplasmic Na ϩ concentrations. This finding indicates that under this particular condition, the pump can function with less than a maximum number of sites filled with Na ϩ ions (5).In sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA), the best characterized P-type pump, ATP hydrolysis can take place without Ca 2ϩ transport to allow for thermogenesis (6). This uncoupling is prominent in the presence of a Ca 2ϩ gradient across the SR membrane. Recent studies have shown that sarcolipin, a small SERCA regulator, increases heat production by this pump (7). This finding demonstrates a regulatory inter...

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“…Our studies showed that mice lacking SLN were sensitive to cold challenge when BAT function was minimized and that reintroduction of SLN rescued the cold-sensitive phenotype, indicating thermogenic function of SLN (Bal et al, 2012). In vitro studies have shown that SLN interacts with sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA) (Odermatt et al, 1998;Sahoo et al, 2015) and causes uncoupling of Ca 2+ transport from ATP hydrolysis, leading to heat production (Mall et al, 2006). Interestingly, SLN expression is developmentally regulated in skeletal muscle of rats, with the expression being relatively high in all skeletal muscles during fetal development and reaching the highest level on the day of birth (Babu et al, 2007).…”

Section: Introductionmentioning

confidence: 81%

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

Pant

Bal

Periasamy

2015

Journal of Experimental Biology

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Neonatal mice have a greater thermogenic need than adult mice and may require additional means of heat production, other than the established mechanism of brown adipose tissue (BAT). We and others recently discovered a novel mediator of skeletal muscle-based thermogenesis called sarcolipin (SLN) that acts by uncoupling sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA). In addition, we have shown that SLN expression is downregulated during neonatal development in rats. In this study we probed two questions: (1) is SLN expression developmentally regulated in neonatal mice?; and (2) if so, will cold adaptation override this? Our data show that SLN expression is higher during early neonatal stages and is gradually downregulated in fast twitch skeletal muscles. Interestingly, we demonstrate that cold acclimation of neonatal mice can prevent downregulation of SLN expression. This observation suggests that SLN-mediated thermogenesis can be recruited to a greater extent during extreme physiological need, in addition to BAT.

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The Presence of Sarcolipin Results in Increased Heat Production by Ca2+-ATPase

Cited by 98 publications

References 35 publications

ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

Capsazepine, a synthetic vanilloid that converts the Na,K-ATPase to Na-ATPase

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

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The Presence of Sarcolipin Results in Increased Heat Production by Ca2+-ATPase

Cited by 98 publications

References 35 publications

ATP consumption by sarcoplasmic reticulum Ca2+ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

ATP consumption by sarcoplasmic reticulum Ca2+ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

Capsazepine, a synthetic vanilloid that converts the Na,K-ATPase to Na-ATPase

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

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ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle

ATP consumption by sarcoplasmic reticulum Ca²⁺ pumps accounts for 50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle